The goal of this proposal is to establish the efficacy and safety of epoxomicin as a potential therapy for the treatment of multiple myeloma, an incurable neoplasm affecting 70,000 Americans, accruing 15,000 new cases yearly, and accounting for 1-2% of cancer-related deaths. It is uniformly fatal, with eighty percent of patients suffering from devastating and progressive bone destruction. The average life span after diagnosis is less than three years, and this has not changed significantly over the past 30 years. Beneficial effects of conventional therapeutic regimens are modest and relapse is invariable. Therefore, there is an urgent need to develop anti-myeloma therapies that are more effective than those currently available. An entirely new approach has recently been suggested for the treatment of myeloma based on the exquisite sensitivity of myeloma cells to the activity of the proteasome, the intracellular machinery responsible for the degradation of many important transcription factors. Proteasome inhibition, as a novel targeted therapeutic approach, is causing substantial and remarkable anti-tumor effects in patients. PS-341, being developed by Millennium Pharmaceuticals and now called Bortezomib, inhibits the 26S proteasome and produces remissions in 20% of patients with advanced myeloma. This notable advance has led to fast-tracking of PS-341 by the FDA. However, remissions are of short duration and the drug is given intravenously. In efforts to remedy these shortcomings, we have examined a series of proteasome inhibitors that exhibit anti-myeloma effects in vitro and in vivo and have focused on epoxomicin, a potent, natural, cell-permeable compound that selectively and irreversibly inhibits proteasome activity and can, potentially to advantage, be given orally. Epoxomicin should convey substantive clinical advantages over PS-341. Efficacy and safety of epoxomicin in reducing myeloma tumor burden and concomitant osteolysis will be demonstrated in two preclinical treatment settings. The first, a preventative model of myeloma, where administration of epoxomicin commences at the time mice are inoculated with myeloma cells (corresponding to patients in clinical remission or plateau phase) and second, a treatment model where administration commences after the tumor is established. Aim 1: Evaluate the effect of epoxomicin on myeloma tumor progression. Aim 2: Evaluate the effect of epoxomicin on the development and progression of myeloma induced osteolytic bone lesions. Aim 3: Determine the effects of epoxomicin on the time to onset of hind-limb paralysis, a surrogate marker of survival. Aim 4: Correlate circulating levels of orally administered epoxomicin with anti-myeloma efficacy. Safety of the compound will be determined by detailed skeletal and soft organ histology, assessment of peripheral blood counts, bone marrow and liver function and serum chemistry. These studies should demonstrate the potential of epoxomicin as a new and effective therapeutic agent for treatment of myeloma patients, with substantially greater specificity, efficacy and ease of use than current treatment modalities. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]